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Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes

Lookup NU author(s): Professor Patrick Chinnery, Professor Robert Lightowlers, Professor Doug Turnbull

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Abstract

Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = 111; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.


Publication metadata

Author(s): Chinnery PF, Howell N, Lightowlers RN, Turnbull DM

Publication type: Article

Publication status: Published

Journal: Brain

Year: 1997

Volume: 120

Issue: 10

Pages: 1713-1721

Print publication date: 01/10/1997

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/120.10.1713

DOI: 10.1093/brain/120.10.1713

PubMed id: 9365365


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